The invention relates to a bionic organ replacement, i.e. an xe2x80x9cartificial liverxe2x80x9d for intracorporeal as well as extracoporeal application.
It is general knowledge that different metabolic processes occur in the human liver. The digestive products are stored and processed in the hepatocytes. In addition, essential importance is attributable to the liver as a detoxification organ.
The different structures of the hepatocytes, the cytoplasm, the fine and rough endoplasmic reticulum, lycosomes, peroxisomes and the Golgi complex with mitochondria, each carrying out their respective different functions. As an example mention is made of the generation of urea, the diamide of carbon dioxide in the mitochondrial matrix of the hepatocytes. The formation of bile, i.e. bile salts and bile pigments is also part of the functions of the liver. The bile fluid which is separated by the hepatocytes as secretion is received by the interlobular gall capillaries and transmitted to the interhepatic gall ducts.
It is the object of the present invention to provide an organ replacement which is capable, in case of existing organ insufficiency or organ failure, to assume said functions, at least in part, and which is suitable for intracorporeal as well as extracorporeal application.
Said object is solved according to the invention by a ureapotetic organ replacement in accordance with claim 1.
The bionic organ replacement has a structure consisting of three groups of hollow textile micro fibers, whereby the hollow micro fibers of each group issue into at least one respectively central liquid conductors, with the hollow micro fibers of the first group being made of proton-conducting material and having perforations for drainage of bile fluid into the interior of the fibers and one of the surfaces of essentially every hollow microfiber of the first group being hydrophilic and lipophilic, whereas the other of the surfaces is hydrophobic and lipophobic, and whereby cell cultures can be grown on the outer surface of all of the hollow micro fibers.
The invention-specific organ replacement is designed in such manner that if hepatocytes are cultured on the surfaces of the hollow micro fibers, said organ replacement is capable of essentially fulfilling all functions of the liver, both intracorporeal as well as extracorporeal. The hollow micro fibers of the structure have textile properties, i.e. they are extremely fine and flexible. They form the capillary vessels of the artificial liver.
The human liver is constructed of approximately 1 to 1.5 million of liver lobules (lobuli hepati), which have a height of approximately 2 mm and a diameter of approximately 1 to 3 mm and consist of liver cells (hepatocytes) which are arranged approximately polyhedrally. The bile which is formed in the liver lobules is drained as secretion via the interlobular gall capillaries and the small gall ducts into the gall bladder (vesica fellea) or via the gall duct (ductus chlodeochus) directly into the small intestine. The interlobular gall capillaries generally have a diameter from 0.1 to 1.5 xcexcm but can, however, in case of obstruction of the bile flow expand to approximately 15 to 20 xcexcm.
The functions of the interlobular gall capillaries in the organ replacement according to the invention are carried out by the hollow micro fibers of the first group. They must be made of a material, the same as the natural gall capillaries, which is proton-conductive. Apatit, for example, as well as some polymers, specifically polytetrafluorethylene, have proven themselves suitable for said purpose. In order to provide the larges possible surface for culturing the cells, preference is given to spongiform hollow micro fibers. In addition, the fibers must be structured in such manner that they will selectively pass the involved metabolites, in other words, they are semi-permeable.
Another requirement consists in that one of the surfaces of each hollow micro fiber of the first group, preferably the inner surface, is lipophobic and hydrophobic and the other surface, preferably the outer surface, lipophilic and hydrophilic. In this fashion decomposition of the cells can be prevented by the bile formed in the hepatocytes. The surfaces of the hollow micro fibers can, for example, be rendered lipophobic or hydrophobic, in other words they can be xe2x80x9csealedxe2x80x9d by a coating with appropriate polymers and ceramic materials. The relevant technology is known to the expert in this field and is therefore not explained in greater detail.
For purposes of draining the bile into the hollow micro fibers of the first group, these are provided with perforations of the entire wall thickness. The perforations in the hollow micro fibers are made during manufacture by means of stretching and laser application. The bile secretion enters into the hollow micro fibers of the first group via the perforations, said hollow micro fibers constituting the synthetic bile capillaries, and is passed from there to one of several fluid conductors which constitute the synthetic small gall ducts.
In addition to the capillaries and ducts for the bile, the human liver has vessel branches originating from the hepatic artery (arteria hepatica) and the portal vein (vena portae) which supply the liver lobes with blood. The surfaces of the hepatocytes are partially enclosed with cell membranes or plasma membranes which function as separation walls vis-a-vis the neighboring hepatocytes, whereby the distance amounts to approximately 100 to 200 xc3x85. Between the star-shaped hepatocytes approaching the central vein (vena centralis) are formed so-called liver sinusoids, having a diameter equal to approximately 9 to 12 xcexcm, in which flows the blood coming from the vessel branches to the central vein. Between the sinusoidal wall, permeable with respect to blood plasma and macromolecule, and the hepatocytes, there are so-called Disse""s spaces.
According to the invention, the branches or capillaries of the human liver coming from the portal vein and the hepatic artery, are formed by the hollow micro fibers of the second and third group. These have, in accordance with the measurements of the real branches, an inner diameter of approximately 1 to 150 xcexcm. According to the properties of the branches of the portal vein and the hepatic artery, the hollow micro fibers of the second and third group have a lower proton conductivity and act as ion- or electrolyte separation membranes.
Ceramic substances and polymers have proven themselves as materials particularly appropriate for said purpose. The hollow micro fibers of the second and third group respectively issue in a central fluid conductor, the synthetic portal vein or the synthetic hepatic artery. They can be made of bio-compatible material customarily employed for artificial vessels.
On the organ replacement according to the invention, a culture of human liver cells is grown, preferably in vitro, until the outer surface of the hollow micro fibers is fully overgrown with human liver cells. The liver cells or hepatocytes have in their center the nucleus. In addition, the liver cells have the so-called mitochondria, which are equipped with multi-semipermeable membranes with a cut-off accuracy in the micro-, ultra- or nano-range, with size and load exclusion, or a combination of both, and in which, among others, enzymatic reactions occur for the supply of energy.
Finally, the Golgi apparatuses are located in the liver cells in sequences, in whose so-called cisterns, lipids can occur.
As soon as sufficient cell growth exists, the organ replacement according to the invention can be surgically inserted into the body under application of immuno-therapeutics. It is hereby possible to introduce the medicaments into the interior of the hollow micro fibers. Needless to say, the artificial liver according to the invention can also be used as an extracorporeal organ replacement.
Insertion of the organ replacement into the human body is a fundamentally possible alternative to the in vitro cell culture growth, so that still healthy liver cells grow incorporeally over the hollow micro fiber structure. Said method of procedure is specifically advisable with only partial liver damage and can, perhaps, be done endoscopically.
The hollow micro fibers of the organ replacement according to the invention have an inner diameter of approximately 0.1 to 50 xcexcm. This corresponds to the inner diameter of the natural vessels. In principle, if needed, artificial vessel with different measurements can be used, provided this is logical and technically executable. Hollow micro fibers of said diameter can be produced, for example, via spinning process. Relative to the details of the properties, the possible raw materials and the manufacturing method, reference is made to the International Application WO97/26225. As is apparent from this publication, the hollow micro fibers of the specified dimensions can be produced with high precision. It is thus possible to keep the variations of diameter and wall thickness of the hollow micro fibers within a range of plus/minus 6% as a result of which uniform structure can be guaranteed.
The hollow micro fibers are preferably arranged in a cross-sectional honey-comb shaped structure. This corresponds, in turn, to the natural structure of the tissue framework around the individual liver lobules. In general, it can be stated that the structure of the hollow micro fibers and appropriate fluid conductors should be adapted, to the extent possible, to the natural structure of the corresponding vessels in order to obtain maximum compatibility with incorporeal use of the invention-specific organ replacement. As an alternative to the honey-comb structure, corrugated cardboard shape arrangement is also conceivable or any other structure which results in maximum surface of cell overgrowth. The size of a honeycomb cell or a corrugated cardboard structure cell preferably corresponds to approximately the size of a human liver lobule.
The bile flows of the liver consist of approximately 97% water, 0.7% bile salt, 0.2% bile pigments, 0.06% cholesterol, 0. 7% inorganic salts, 1% fatty acids, lecithin and 0.1% fat. The metabolism of the liver is determined by the activity of the human being, by the basic energy need as well as by the food supply. On average, approximately 600 ml bile fluid are generated each day. For that reason, the number and size of the perforations is preferably designed in such fashion so that the resulting bile flow amounts to approximately 100 to 3000 ml per day. Naturally, the design may also call for a lower amount of bile fluid, for example if the invention-specific organ replacement is to substitute only a portion of the human liver. As a rule, a diameter of perforations have proven adequate which is approximately equal to the diameter of the filament lumen of the hollow micro fiber, whereby the total area of perforations should be about 30% if fiber surface.
The hollow micro fibers preferably have a delayed degradation capability and are adjustably degradable. As a result, the service life of the hollow micro fibers can be adapted to the age of the person whose liver is to be substituted by the organ replacement according to the invention.
According to a particularly preferred specific embodiment, the organ replacement according to the invention comprises a porto-caval shunt. This has the benefit of redundancy.